Endocrine pharmacology - Pharmacology for Medical Graduates, 4th Updated Edition

Hypothalamus produces releasing and inhibitory hormones that control pituitary secretion ( Fig. 9.1 ). Hypothalamus controls the secretion of anterior pituitary through portal circulation that carries the releasing and inhibitory hormones. Posterior pituitary is the direct extension of hypothalamus.

Regulation of anterior pituitary hormone synthesis and release. ⊖, Inhibition.

• 1.

  Growth hormone (GH)

• 2.

  Prolactin (PRL)

• 3.

  Gonadotropins (follicle-stimulating hormone [FSH] and luteinizing hormone [LH])

• 4.

  Adrenocorticotropic hormone (ACTH)

• 5.

  Thyrotropin- or thyroid-stimulating hormone (TSH)

• 6.

  Melanocyte-stimulating hormone (MSH)

Growth hormone–releasing hormone (GHRH).

It stimulates anterior pituitary to synthesize and release growth hormone. It is used rarely for testing growth hormone responsiveness.

Growth hormone.

It is a peptide hormone released by anterior pituitary. Its secretion is regulated by hypothalamic hormones.

Functions of growth hormone.

It has growth-promoting effect; produces anabolic effect on muscle. It maintains positive nitrogen balance; promotes utilization of fat.

Clinical disorders of growth hormone ( fig. 9.2 )

Clinical disorders of growth hormone.

Uses.

Recombinant human GH (somatropin and somatrem) is available for parenteral administration. It is used to treat

• ■

  Growth hormone deficiency in children and adults. Following early initiation of treatment with GH in children, stature can be almost normal. In adults, body fat is reduced.

• ■

  AIDS-related wasting.

Mecasermin is a recombinant human IGF-1 (insulin-like growth factor 1). It is administered parenterally to promote growth in children with IGF deficiency not responding to GH. The adverse effects are hypoglycaemia (can be avoided by giving the drug after food) and lipodystrophy.

Somatostatin.

It is a peptide hormone secreted by pancreas and parts of the central nervous system (CNS) in addition to hypothalamus. Somatostatin inhibits release of growth hormone, glucagon, insulin and gastrin. Other actions include constriction of hepatic, splanchnic and renal blood vessels. It has a very short half-life (1–3 minutes). Hence, its synthetic analogue octreotide is preferred for therapeutic use.

Octreotide.

It is more potent and longer acting than somatostatin. Unlike somatostatin, it mainly inhibits growth hormone secretion. It can be administered subcutaneously and intravenously.

Uses of octreotide

• 1.

  Acromegaly.

• 2.

  Symptomatic treatment of various hormone-secreting tumours, e.g. carcinoid syndrome.

• 3.

  Diarrhoea associated with diabetes.

• 4.

  Acute control of bleeding from oesophageal varices. It constricts hepatic blood vessels and decreases variceal bleeding.

The common side effects of octreotide are nausea, diarrhoea and abdominal cramps.

Lanreotide.

It is a somatostatin analogue with a long duration of action.

Drugs used to treat acromegaly

• 1.

  Somatostatin analogues: Octreotide is used to treat acromegaly when surgery and irradiation are contraindicated. It acts by inhibiting synthesis and release of growth hormone. Lanreotide can also be used.

• 2.

  Dopamine-receptor agonists: Dopamine agonists like bromocriptine and cabergoline stimulate the secretion of GH in normal subjects but paradoxically decrease GH secretion in patients with acromegaly. Hence, they can be used to treat acromegaly when patients are unwilling to take regular injection.

• 3.

  Pegvisomant (GH-receptor antagonist): It is used subcutaneously to treat acromegaly in patients not responding to somatostatin analogues.

Thyrotropin-releasing hormone.

Thyrotropin-releasing hormone (TRH) is now rarely used to diagnose thyroid disorders as very sensitive assays for thyrotropin and thyroid hormones are now available.

Corticotropin-releasing hormone.

Corticotropin-releasing hormone (CRH) stimulates release of ACTH from anterior pituitary. CRH is used only for diagnosis of hypercorticism to distinguish between Cushing disease and ectopic ACTH secretion.

Gonadotropin-releasing hormone.

Pulsatile gonadotropin-releasing hormone (GnRH) secretion stimulates gonadotroph cells in the anterior pituitary to synthesize and release LH and FSH. Sustained nonpulsatile administration of GnRH or its analogues can be used for initial stimulation and later suppression of gonadal hormone secretion.

Gonadotropins (GNS)

Follicle-stimulating hormone.

The functions of FSH are

In females	–	development of ovarian follicles
	–	ovarian steroidogenesis
In males	–	regulation of spermatogenesis
	–	conversion of testosterone to oestrogen in Sertoli cells.

Preparations of FSH

• Urofollitropin – obtained from urine of postmenopausal women

• Follitropin alfa and follitropin beta – recombinant forms of FSH

Luteinizing hormone.

The functions of LH are

In females	–	ovarian steroidogenesis
	–	ovulation
In males	–	testosterone production by Leydig cells

Preparations of LH.

Lutropin, recombinant form of LH, is available for use.

Human chorionic gonadotropin.

It is secreted by placenta – helps to maintain corpus luteum of pregnancy. It exerts its actions through LH receptors. Human chorionic gonadotropin (hCG) purified from urine and a recombinant form of hCG are available for use.

Uses of FSH, LH and HCG

• ■

  For controlled ovarian hyperstimulation in assisted reproduction technology.

• ■

  Stimulation of spermatogenesis in hypogonadal infertile males.

Adverse effects of FSH, LH and HCG.

Ovarian hyperstimulation syndrome and multiple pregnancy in females; gynaecomastia in males.

Gonadorelin.

It is a synthetic human GnRH. Pulsatile administration stimulates the release of FSH and LH → increased release of oestrogen and progesterone. It has a short duration of action; is administered i.v. or s.c.; useful to test function of pituitary – gonadal axis.

GNRH analogues (superactive GNRH agonists).

For example:

GnRH analogues are commonly administered subcutaneously. Nafarelin is available as nasal spray.

Uses of GNRH analogues

• ■

  Prostatic carcinoma

• ■

  Precocious puberty

• ■

  Breast cancer in premenopausal women

• ■

  Uterine fibroid, endometriosis

• ■

  Polycystic ovarian disease

• ■

  Controlled ovarian hyperstimulation in assisted reproduction

Adverse effects.

Hot flushes, loss of libido and vaginal dryness can occur.

Gnrh antagonists.

For example:

• ■

  Males: Decrease testosterone level; useful in advanced prostate cancer

• ■

  Females: To suppress LH surge during controlled ovarian hyperstimulation

Advantages of GnRH antagonists over GnRH agonists include quick onset of action and lower risk of ovarian hyperstimulation syndrome.

Prolactin.

Prolactin is a peptide hormone secreted by anterior pituitary. It is also known as mammotropin or lactogenic hormone.

Control of prolactin secretion is mainly inhibitory unlike other anterior pituitary hormones ( Fig. 9.3 ). Dopamine, secreted by hypothalamus, inhibits prolactin secretion. Thus, dopamine agonists (bromocriptine, cabergoline) inhibit prolactin secretion whereas dopamine antagonists (e.g. chlorpromazine, haloperidol, metoclopramide) cause increase in prolactin levels.

Regulation of prolactin secretion. PRH, prolactin-releasing hormone; PRIH, prolactin-release inhibitory hormone.

Hyperprolactinaemia.

This is a relatively common condition resulting from hypothalamic or pituitary disorders. The common causes are prolactin-secreting pituitary adenomas and dopamine antagonists. For prolactin-secreting tumours, treatment options are surgery, irradiation and drugs. Postoperatively, most of the patients require treatment with dopamine-receptor agonists. These drugs decrease both prolactin secretion and size of adenoma.

Dopamine-receptor agonists.

Bromocriptine is the prototype of ergot-derived dopamine agonist. Other ergot derivatives used to treat hyperprolactinaemia are pergolide and cabergoline .

Bromocriptine.

It is a semisynthetic ergot derivative acting as a potent dopamine agonist (mainly at D ₂ -receptors). As dopamine is a neurotransmitter at different sites in the brain, it produces various motor, behavioural and endocrine effects.

Pharmacological actions

• 1.

  Endocrine:

  • (a)

    Dopamine (prolactin release–inhibiting hormone, PRIH) is the main factor controlling prolactin secretion. Bromocriptine, a dopamine agonist, effectively reduces the secretion of prolactin.

  • (b)

    Bromocriptine increases GH level in normal individuals, but in patients with acromegaly, it acts paradoxically to reduce GH levels.

• 2.

  It relieves symptoms of parkinsonism that results from dopamine deficiency in nigrostriatal pathway.

• 3.

  Nausea and vomiting may occur with bromocriptine due to stimulation of dopamine receptors in chemoreceptor trigger zone (CTZ).

• 4.

  It may cause hypotension due to α-adrenergic blockade.

Pharmacokinetics.

Bromocriptine is partly absorbed after oral administration, undergoes first-pass metabolism extensively and metabolites are excreted in bile.

Uses.

It is useful in hyperprolactinaemia, acromegaly, parkinsonism and restless leg syndrome.

Adverse effects

• 1.

  Gastrointestinal tract (GIT): Nausea, vomiting and constipation

• 2.

  Cardiovascular system (CVS): Postural hypotension – due to α-adrenergic blockade

• 3.

  CNS: Hallucinations, confusion and psychosis

Cabergoline.

It is more potent and longer acting than bromocriptine. It is the preferred drug for hyperprolactinaemia. It is also useful in acromegaly.

• 1.

  Iodide trapping: Active transport of iodide ions (I ⁻ ) into follicular cells of thyroid gland is known as iodide trapping and takes place by a basement membrane protein called sodium/iodide symporter.

• 2.

  Oxidation and iodination: The iodide ion is oxidized to iodine by peroxidase enzyme. Iodine combines with tyrosine residues of thyroglobulin molecule and forms monoiodotyrosine (MIT) and diiodotyrosine (DIT).

• 3.

  Coupling: This is the final step in the synthesis of thyroid hormones and is catalysed by thyroid peroxidase. Two molecules of DIT couple to form thyroxine (T ₄ ) and one molecule of MIT with one molecule of DIT forms triiodothyronine (T ₃ ).

  $\text{MIT + DIT →}n{\text{T}}_{\text{3}}\text{; DIT + DIT →}n{\text{T}}_{\text{4}}$

• 4.

  Hormone release: Release of thyroid hormones takes place under the control of TSH. The process involves endocytosis and proteolysis of iodinated thyroglobulin and results in release of T ₄ , T ₃ , MIT and DIT.

• 5.

  Peripheral conversion of T ₄ to T ₃ : Most of the hormone released from thyroid is T ₄ , which is less potent than T ₃ . Conversion of T ₄ to T ₃ occurs mainly in liver and kidney. Peripheral conversion of T ₄ to T ₃ is inhibited by propylthiouracil, iopanoic acid, propranolol and glucocorticoids.

Differences between T ₃ and T ₄

T 3 (Triiodothyronine)	T 4 (Thyroxine)
Formed by DIT + MIT = T 3	Formed by DIT + DIT = T 4
Relatively rapid onset of action	Slower onset of action
Short duration of action (half-life: 1 day)	Long duration of action (half-life: 7 days)
More potent than T 4	Less potent
Useful to treat myxoedema coma	Used to treat myxoedema coma and for regular treatment of myxoedema

Mechanism of action.

Mechanism of action of thyroid hormones is similar to that of steroid hormones. Thyroxine needs to be converted into T ₃ inside the cell for binding to nuclear receptor.

Preparations

• 1.

  Levothyroxine sodium (T ₄ ): tablets and parenteral preparation (i.v.)

• 2.

  Liothyronine (T ₃ , triiodothyronine): oral tablets, parenteral preparation (not commonly available)

• 3.

  Combination of T ₄ and T ₃ (4:1): tablets

Therapeutic uses.

Replacement therapy in hypothyroid states

• 1.

  Cretinism and myxoedema: For cretinism, treatment of newborn should be started as early as possible after birth to ensure normal growth and cognitive development. Replacement in elderly and patients with coronary artery disease should be started with low dose of levothyroxine sodium such as 12.5–25 mcg daily and slowly increased to prevent precipitation of ischaemia and myocardial infarction. In young adults with hypothyroidism, full replacement doses of levothyroxine sodium can be administered (50–100 mcg daily as a single dose orally in the morning on an empty stomach). The goal of therapy is to relieve symptoms and restore serum TSH to normal levels; treatment is for lifetime.

• 2.

  Myxoedema coma: This is a medical emergency and usually common in long-standing untreated myxoedema cases. It is usually precipitated by infection or other forms of stress.

  • Diagnosis

    • ■

      Clinical features: Hypothermia, bradycardia, pleural effusion, pericardial effusion with coma.

    • ■

      History of previous thyroid surgery or replacement therapy with poor compliance.

    • ■

      Estimation of plasma levels of T ₃ , T ₄ and TSH.

    • ■

      Treatment should be started based on clinical features without waiting for confirmation.

  • Treatment

    • (a)

      Levothyroxine, intravenously (i.v.)

    • (b)

      Intravenous hydrocortisone

    • (c)

      Correction of hypothermia by warming the patient

    • (d)

      Correction of electrolyte imbalance, e.g. hyponatraemia

    • (e)

      Ventilatory support may be required

    • (f)

      Antibiotics, if infection is the precipitating cause

• 3.

  Benign thyroid nodule – some cases, therapy with T ₄ suppresses TSH levels.

• 4.

  Thyroid carcinoma – thyroid hormone suppression therapy is used in papillary carcinoma of thyroid to suppress TSH and prevent its stimulation of growth of tumour.

These drugs reduce the level of thyroid hormones by reducing thyroid hormone synthesis or release or both. These drugs play an important role in the management of hyperthyroidism caused by both benign and malignant conditions of thyroid gland.

Synthesis, storage and secretion of thyroid hormones and drugs affecting them.

• Site 1: Thiocyanates, perchlorates, excess iodides

• Sites 2 and 3: Iodides, thioamides

• Site 4: Iodides

• Site 5: Propylthiouracil, propranolol, iopanoic acid, ipodate, glucocorticoids

• Site 6: Radioactive iodine (destruction of thyroid tissue)

Testosterone is the main androgen in men. It is synthesized by Leydig cells (interstitial cells) of the testes under the influence of interstitial cell-stimulating hormone, ICSH (LH) of anterior pituitary. FSH is responsible for spermatogenesis ( Fig. 9.6 ).

Androgen synthesis and regulation. Testosterone (but not dihydrotestosterone) mediates negative feedback inhibition. GnRH, gonadotropin-releasing hormone; FSH, follicle-stimulating hormone; LH, luteinizing hormone.

• 1.

  Physiological antagonist: Oestrogens.

• 2.

  Testosterone synthesis inhibitors : Ketoconazole, spironolactone.

• 3.

  Androgen-receptor antagonists : Flutamide, bicalutamide, cyproterone, spironolactone.

• 4.

  5α-reductase inhibitors : Finasteride, dutasteride.

The mechanism of action of antiandrogens is shown in Fig. 9.7 .

• ■

  Oestrogens decrease androgen levels by inhibiting gonadotrophin secretion.

• ■

  Ketoconazole is an antifungal agent that inhibits adrenal and gonadal steroid synthesis.

• ■

  Spironolactone is an aldosterone antagonist that inhibits testosterone synthesis; it is also a competitive blocker of androgen receptors. The side effects are hyperkalaemia, gynaecomastia and menstrual irregularities.

• ■

  Cyproterone acetate and flutamide competitively block androgen receptors. They block the action of androgens on the target cell. These drugs are used to treat carcinoma of prostate, hirsutism in females and acne in both sexes. Adverse effects are impotence, hot flushes, gynaecomastia, hepatic damage, decreased spermatogenesis and gastrointestinal (GI) side effects such as nausea, vomiting and diarrhoea. Bicalutamide (oral) is more potent, longer acting and better tolerated than flutamide.

• ■

  Finasteride and dutasteride block the conversion of testosterone to dihydrotestosterone by inhibiting 5α-reductase enzyme. Dutasteride is slow acting but has long duration of action. Given orally, they decrease serum and prostatic dihydrotestosterone levels. Dihydrotestosterone is more active and is responsible for most of the actions of androgens in many tissues. These drugs decrease the size of prostate and improve urinary flow rate. They are less effective when compared to surgery and α ₁ -blockers in the treatment of BPH. Combined use of finasteride and α ₁ -adrenergic blockers results in better effect. Prolonged treatment is necessary to sustain benefit. Stoppage of the drug results in regrowth of the prostate. They are also useful in male pattern baldness. The side effects of finasteride are impotence, skin rashes, itching and decreased libido.

Mechanism of action of antiandrogens. ⊖, inhibition.

It is a nonsteroidal compound and has antioestrogenic effect.

Mechanism of action

• ■

  Pure oestrogen antagonist.

• ■

  Useful in breast carcinoma, not responding to tamoxifen.

Tamoxifen, raloxifene and ormeloxifene are selective oestrogen-receptor modulators (SERMs) and have tissue-selective actions; oestrogen-like actions in some and oestrogen antagonistic actions in other tissues.

It is a nonsteroidal compound with a selective ER-modulating effect.

Actions

• 1.

  Uterus: It causes endometrial proliferation.

• 2.

  Bone: It decreases the rate of resorption of bone by inhibiting the activity of osteoclasts.

• 3.

  Plasma lipids: It reduces blood cholesterol and LDL levels and decreases the risk of cardiovascular disease.

Raloxifene has high affinity for both ERα and ERβ.

Actions

Raloxifene is rapidly absorbed after oral administration but has poor bioavailability due to extensive first-pass metabolism. It is used for prevention and treatment of osteoporosis in postmenopausal women. The adverse effects are hot flushes, leg cramps, increased incidence of deep vein thrombosis and pulmonary embolism. It does not increase the risk of endometrial cancer.

Ormeloxifene, a selective oestrogen-receptor modulator, has antagonistic effect on breast and uterus. It is useful for the treatment of dysfunctional uterine bleeding. Adverse effects include headache, weight gain and nausea.

• ■

  Exemestane (steroidal agent) causes irreversible inhibition; letrozole and anastrozole (nonsteroidal agents) cause reversible inhibition of aromatase. They are administered orally.

• ■

  They decrease oestrogen levels by inhibiting aromatase enzyme – useful in breast carcinoma; hot flushes are common adverse effects.

• ■

  Unlike tamoxifen, there is no endometrial hyperplasia, venous thromboembolism, and unfavourable effect on lipid profile. But it causes bone loss. It should not be administered to premenopausal women.

  

Same as other steroidal hormones. The density of progesterone receptors is controlled by oestrogens.

• 1.

  Natural progestin : Progesterone

• 2.

  Synthetic progestins include progesterone and 19 – nortestosterone derivatives ( Table 9.3 )

  Table 9.3 ■

  Synthetic progestins

  Progesterone derivatives	19-Nortestosterone derivatives
  • Medroxyprogesterone acetate	• Norethindrone (norethisterone)
  • Hydroxyprogesterone caproate	• Norgestrel
  • Megestrol acetate	• Levonorgestrel
  	• Desogestrel
  	• Gestodene
  	• Norgestimate

The progesterone derivatives have weak anti-ovulatory effect. Desogestrel, gestodene and norgestrel have potent anti-ovulatory effect, minimal/no androgenic effect, no unfavourable effect on lipid profile.

Progesterone is not effective orally because of extensive first-pass metabolism. It is usually given by i.m. route in oil base. Micronized progesterone and synthetic progestin preparations are effective orally.

Progestins are commonly used for contraception and HRT of postmenopausal women ( Fig. 9.11 ).

• 1.

  Contraception: Progestins are used in contraception as combined pill (oestrogen-progestogen), minipill, postcoital pill, injectable preparations, implants and intrauterine contraceptive devices. For details, see under contraceptives (see p. 326).

• 2.

  Dysfunctional uterine bleeding: Oral progestins (norethisterone or norethynodrel) are used. A high initial dose is used to arrest bleeding after which maintenance dose is given for 20 days. Withdrawal bleeding occurs in 2–5 days after stoppage of therapy. The cyclic treatment can be continued for 3–6 months.

• 3.

  Endometriosis: The classical symptoms are dysmenorrhoea, dyspareunia, menorrhagia and infertility. Continuous long-term treatment with oral progestins causes regression of the lesion by inducing anovulatory cycles.

• 4.

  HRT in postmenopausal women: Progestins are combined with oestrogens for long-term HRT in women with an intact uterus to prevent endometrial proliferation and subsequent carcinoma.

• 5.

  Endometrial carcinoma: They are used in advanced metastatic endometrial carcinoma.

• 6.

  Postponement of periods: Either progestins or combined oral contraceptive pills should be started 3 days before the expected period and continued till required time as needed. The withdrawal bleeding occurs within 72 hours after stoppage of the drug.

Uses of progestins.

The adverse effects are acne, fluid retention, weight gain, depression, irregular periods, hirsutism, increase in blood glucose levels (levonorgestrel) and increased risk of breast cancer on prolonged use. The older progestins cause altered plasma lipid levels; hence, there is an increased risk of cardiovascular diseases. The newer progestins have little or no adverse effect on lipid levels.

• 1.

  Termination of pregnancy : Mifepristone is used in combination with prostaglandins (PGs) for termination of early pregnancy. A single oral dose of 600 mg of mifepristone, followed 48 hours later by gemeprost (PGE ₁ ) 1 mg vaginal pessary, raises the success rate to 95%.

• 2.

  Contraception : It has been used as a postcoital contraceptive. It causes sloughing and shedding of decidua and brings about abortion.

• 3.

  Used for the induction of labour in cases of intrauterine fetal death.

• 4.

  For cervical ripening before abortion or induction of labour.

• 5.

  Hypercortisolism : It has antiglucocorticoid activity, hence useful in Cushing syndrome.

These are nausea, vomiting, diarrhoea, abdominal pain, headache, uterine bleeding and teratogenicity.

They include combined pills, minipills and postcoital pills.

Combined oestrogen and progestin preparations (combined pill)

The combined oral contraceptive pill is widely used; it is the most effective reversible method of contraception.

In combined pill

• ■

  Oestrogen used: ethinyl oestradiol.

• ■

  Commonly used progestins: Norethindrone, levonorgestrel, norgestimate, norgestrel, desogestrel and gestodene.

• ■

  The combination is synergistic. In addition, progestins inhibit oestrogen-induced endometrial proliferation → decrease risk of endometrial carcinoma.

• ■

  Each pill ( monophasic ) taken throughout the treatment period has a fixed amount of oestrogen and progestin.

• ■

  In biphasic preparation , the dose of oestrogen is kept constant but progestogen varies according to the phase of the menstrual cycle. In triphasic preparation , the dose of oestrogen is slightly more in mid-cycle but doses of progestin increase in three successive phases of menstrual cycle.

The oestrogen content of pills usually ranges from 20 to 30 mcg and the progestin content from 0.1 to 1 mg in monophasic pills. Preparations containing less than 30 mcg of oestrogen are referred to as ‘low-dose’ pills. The progestins namely desogestrel, gestodene and norgestimate are ‘lipid friendly’, as they increase HDL level and reduce atherogenic risk. They have potent antiovulatory effect.

Mechanism of action of combined contraceptive pill.

The following are the mechanism of action of contraceptives ( Fig. 9.13 ). The numerals 1, 2, 3 and 4 shown in the figure are described in the following ways:

• 1.

  Both oestrogen and progestin act synergistically on hypothalamic–pituitary axis by negative feedback mechanism and inhibit the release of FSH and LH, which leads to inhibition of ovulation.

• 2.

  Cause tubal and uterine contractions that may interfere with fertilization.

• 3.

  Make the endometrium less suitable for implantation.

• 4.

  Thick, viscid cervical mucus secretion prevents sperm penetration (progestins).

Mechanism of action of contraceptives.

Schedule for use of combined pill.

The schedule for use of combined pill is shown in Fig. 9.14.

Schedule for use of combined pill.

The combined oral contraceptive pill is usually started from first day of menstrual cycle (i.e. the day bleeding starts) and continued till day 21. Days 22–28 is oral contraceptive pill–free period (7 days). The next day (i.e. after day 28) is taken as day 1 and the course of the combined pill repeated as above till required period of contraception.

The combined pill can also be started from fifth day of menstrual cycle, continued for 21 days followed by a gap of 7 days, following which it is continued again.

If a woman on combined oral contraceptive pills fails to take a tablet, she should take two tablets the next day and continue rest of the pills as prescribed. If she misses more than two tablets, she should stop the treatment, use alternate method of contraception and restart course of pills from next cycle.

Contraindications of combined oral contraceptives.

Absolute contraindications include thromboembolic disorders, malignancy of genital tract, severe hypertension, cardiac diseases, porphyria and active liver disease.

Relative contraindications are obesity, diabetes, migraine, mild hypertension, uterine fibroid, etc.

Progestin-only pill (minipill)

Minipill contains very low dose of a progestin (norethindrone or norgestrel) only. It may be used in women if oestrogens are contraindicated. The schedule for use of minipill is shown in Fig. 9.15 .

Schedule for use of minipill.

Mechanism of action of minipill.

It acts by altering cervical mucus, interfering with implantation and inhibiting ovulation. It may cause menstrual irregularities and there is increased risk of ectopic pregnancy.

Intrauterine devices:

• (a)

  Levonorgestrel device: It is a ‘T’-shaped device inserted into the uterine cavity and the contraceptive effect lasts for 5 years.

• (b)

  Progestasert: Intrauterine device containing progestogen can be inserted into the uterine cavity. The efficacy is low and the device has to be replaced yearly.

Most of the side effects with combined oral pills are dose related. The current low-dose preparations have minimal side effects.

• 1.

  Nausea, vomiting, headache, breakthrough bleeding, which occurs initially during therapy but subside following continuous use.

• 2.

  Weight gain, fluid retention, acne and pigmentation of skin occur later.

• 3.

  Impaired glucose tolerance and alteration in lipid profile was observed with high-dose contraceptives and is rare with low dose, newer preparations.

• 4.

  Blood pressure may increase following long-term use. It is less common with low-dose preparations.

• 5.

  Long-term adverse effects include increased incidence of venous thromboembolic disease especially in women with risk factors for thromboembolism like smoking; risk of myocardial infarction and stroke in women with coexisting diabetes or hypertension.

• 6.

  Increased risk of gallstones, benign liver tumours and breast cancer on prolonged use.

Rifampin, phenytoin and carbamazepine induce hepatic microsomal enzyme system, enhance metabolism of oral contraceptives and can cause failure of contraception. Hence, when the woman is on rifampin, phenytoin, etc., alternative forms of contraception should be used.

Oral contraceptives × tetracyclines/ampicillin .

Oestrogens are conjugated in liver and excreted via bile into the gut, where they are deconjugated by bacterial flora and then reabsorbed. Antibiotics (tetracyclines, ampicillin) are incompletely absorbed in the gut, so they destroy the bacteria, therefore, reduce deconjugation and reabsorption of oral contraceptives, leading to contraceptive failure.

Some of the drugs tried as male contraceptives are oestrogens, progestins, androgens, antiandrogens, GnRH analogues, gossypol, etc.; but the results are not satisfactory.

The mechanism of action of steroid hormones is given in Fig. 9.18 .

Mechanism of action of steroid hormones. H, hormone; R, receptor; SRC, steroid receptor complex.

For classification and important features of corticosteroids, see Table 9.6 , p. 334.

Corticosteroid with predominant sodium- and water-retaining property, e.g. aldosterone and desoxycorticosterone are mineralocorticoids. Corticosteroid with predominant liver glycogen deposition and gluconeogenic effects, e.g. hydrocortisone (cortisol) and cortisone, are glucocorticoids ( Table 9.6 ). The two actions (mineralocorticoid and glucocorticoid) are not completely separated in naturally occurring steroids, whereas synthetic preparations are available with selective action.

Carbohydrate metabolism

The net result is (i) hyperglycaemia, (ii) decreased tissue sensitivity to insulin and (iii) diabetes may be exacerbated. Therefore, glucocorticoids are (relatively) contraindicated in diabetics.

Protein metabolism

Calcium metabolism (anti-vitamin d action)

Prolonged use of these drugs may lead to osteoporosis and pathological fracture of vertebral bodies.

Glucocorticoids have sodium and water retaining property; exert a permissive effect on pressor action of adrenaline and angiotensin. On chronic administration, these drugs may cause hypertension and worsening of CCF (congestive cardiac failure).

Corticosteroids are required for the normal function of skeletal muscles. Weakness occurs in both hypocorticism and hypercorticism.

Prolonged use of glucocorticoids may cause muscle wasting and weakness (steroid myopathy).

Corticosteroids have a number of indirect effects on CNS through maintenance of (i) blood pressure, (ii) blood glucose concentration and (iii) electrolyte levels.

They also have direct effects on CNS and influence mood and behaviour. Patients with Addison disease show depression, irritability and even psychosis. On the other hand, glucocorticoid therapy can cause euphoria, insomnia, restlessness and psychosis.

Glucocorticoid therapy leads to a decrease in the number of circulating lymphocytes, eosinophils, basophils and monocytes. This is due to redistribution of cells. They have a marked lympholytic action, therefore are used in lymphomas and leukaemias.

They have powerful anti-inflammatory and immunosuppressant effects. They prevent or suppress the clinical features of inflammation such as redness, heat, pain and swelling. At tissue level, they suppress the early phenomena (capillary permeability, oedema, cellular infiltration and phagocytosis) and late responses like capillary proliferation, collagen deposition, fibroblast activity and scar formation.

• 1.

  Glucocorticoids induce a protein called lipocortin which inhibits phospholipase A ₂ ; hence, PGs, leukotrienes (LTs) and PAF are not formed.

• 2.

  Production of cytokines like IL-1, IL-6 and TNF-α necessary for initiating inflammation is inhibited.

• 3.

  Chemotaxis is suppressed.

• 4.

  Glucocorticoids stabilize lysosomal membrane and prevent release of inflammatory mediators.

• 5.

  Glucocorticoids inhibit expression of various adhesion molecules on endothelial cells, thus inhibiting leucocyte migration to site of injury.

Glucocorticoids have immunosuppressant effect. They inhibit both B-cell and T-cell lymphocyte functions and this results in impairment of humoral and cell-mediated immunity. Cell-mediated responses are suppressed indirectly by inhibiting the production of cytokines, including TNF-α and interleukins. They also suppress all types of hypersensitivity or allergic reactions.

A single dose of glucocorticoids is practically harmless, rather they are life-saving drugs in conditions like anaphylactic shock and acute adrenal insufficiency. The use of glucocorticoids in supraphysiological doses for more than 2–3 weeks causes a number of undesirable effects. Most of the adverse effects are extension of their pharmacological actions.

• 1.

  Metabolic effects : Hyperglycaemia, or aggravation of pre-existing diabetes.

• 2.

  Cushing’s habitus : Abnormal fat distribution causes peculiar features with moon face, buffalo hump and thin limbs.

• 3.

  GIT : Peptic ulceration, sometimes with haemorrhage or perforation.

• 4.

  Salt and water retention : Mineralocorticoid effect may cause oedema, hypertension and even precipitation of CCF, particularly in patients with primary hyperaldosteronism. This can be minimized by using synthetic steroids like dexamethasone and betamethasone.

• 5.

  Muscle : Steroid treatment can cause hypokalaemia leading to muscle weakness and fatigability. Long-term steroid therapy leads to steroid myopathy.

• 6.

  Bone : Osteoporosis with pathological fractures of vertebral bodies is common. Ischaemic necrosis of femoral head can also occur.

• 7.

  Growth retardation in children is more common with dexamethasone and betamethasone.

• 8.

  Eye : Glaucoma and cataract may occur on prolonged therapy.

• 9.

  CNS : Behavioural disturbances like nervousness, insomnia, mood changes and even psychosis may be precipitated.

• 10.

  Long-term therapy with steroids leads to immunosuppression, which makes the patient vulnerable to opportunistic infections like fungal (candidiasis, cryptococcosis), viral (herpes, viral hepatitis) and bacterial (reactivation of latent tuberculosis). Inhalational steroids can cause local irritation and fungal infection of upper respiratory tract, which can be prevented by the use of spacer and by rinsing the mouth after inhalation.

• 11.

  Hypothalamic–pituitary–adrenal (HPA) axis suppression : The most dangerous side effect of long-term steroid therapy is HPA axis suppression. Long-term use of corticosteroids in large doses will decrease ACTH secretion through negative feedback effect on hypothalamus and pituitary and gradually cause adrenal cortical atrophy. Hence, abrupt stoppage of glucocorticoid therapy following prolonged use leads to:

  • ■

    Flaring up of the underlying disease being treated.

  • ■

    Withdrawal symptoms like fever, myalgia, arthralgia and malaise.

  • ■

    Acute adrenal insufficiency on exposure to stress which manifests as anorexia, nausea, vomiting, abdominal pain, hypotension, dehydration, hyponatraemia, hyperkalaemia, etc.

Therefore, important precautions to be taken during long-term steroid therapy to minimise HPA axis suppression are as follows:

• (a)

  Whenever possible, topical use is preferred.

• (b)

  Short- or intermediate-acting steroids (e.g. hydrocortisone, prednisolone) should be preferred.

• (c)

  Give steroids as a single morning dose at 8 a.m.; if the daily dose is high, administer two-third of the dose in the morning and one-third in the evening, which will mimic endogenous hormone levels and minimize chances of HPA axis suppression.

• (d)

  Try alternate-day steroid therapy in chronic conditions like bronchial asthma, nephrotic syndrome and systemic lupus erythematosus (SLE).

• (e)

  Withdrawal of steroids after long-term (>2 weeks) treatment should be very slow to allow recovery of normal adrenocortical function. The doses of steroid should be tapered gradually and then stopped. It will take days/weeks or even longer for HPA axis to recover after stoppage of therapy. During this period, patient will require treatment with steroids on exposure to stress.

• Note: If a patient on long-term steroid therapy is exposed to stress like infections and major surgery, the dose of steroids administered should be increased to combat stress (as adrenals will fail to increase glucocorticoid secretion on account of HPA axis suppression).

Metyrapone: It blocks formation of hydrocortisone, hence useful to test the integrity of HPA axis and to treat hypercortisolism due to adrenal tumours.

Mifepristone: It has antiglucocorticoid, antiandrogenic actions and is a competitive antagonist of progesterone. It is useful in adrenal carcinoma.

Insulin was discovered by Banting and Best. Insulin is synthesized by the β-cells of pancreatic islets from a single-chain polypeptide precursor called preproinsulin, which is converted to proinsulin. Insulin is formed by the removal of C-peptide from proinsulin by proteolysis. Insulin consists of two peptide chains called A and B ( Fig. 9.19 ). These two chains are connected by two disulphide bridges. C-peptide (connecting peptide) can produce immunogenic reactions.

Structure of proinsulin.

Regulation of insulin secretion

Insulin secretion is regulated by chemical, neural and hormonal mechanisms.

Chemical.

Glucose, amino acids and fatty acids in the blood stimulate β-cells and release insulin ( Fig. 9.20 ). Ingestion of nutrients (carbohydrate/protein/fat) causes release of gut peptides (incretins) like GLP-1 (glucagon-like peptide) and GIP (glucose-dependent insulinotropic polypeptide) which promote the secretion of insulin. Oral nutrients (including glucose) are more effective in stimulating incretin secretion as compared to their intravenous infusion.

Regulation of insulin secretion.

Neural.

Both parasympathetic and sympathetic fibres supply the islet cells. Parasympathetic stimulation causes increase in insulin secretion and lowers raised blood glucose level. The islet cells have both α-adrenergic and β-adrenergic receptors. Adrenergic β ₂ -stimulation increases insulin release and the blood glucose falls. Adrenergic α ₂ -activation causes hyperglycaemia by inhibiting the release of insulin.

Hormonal.

Counter-regulatory hormones like adrenaline, cortisol and glucagon promote glucose release from liver. Glucagon stimulates whereas somatostatin inhibits insulin release ( Fig 9.21 ).

Effect of various hormones on blood glucose level.

Actions of insulin ( fig. 9.22 )

Insulin has profound effects on the metabolism of carbohydrate, fat and protein. It facilitates the entry of glucose into all cells of the body. However, entry of glucose into RBCs, WBCs, liver and brain cells can occur independent of insulin. Exercise also facilitates entry of glucose into muscle cells without the need for insulin.

• 1.

  Insulin inhibits hepatic glycogenolysis and gluconeogenesis; inhibits lipolysis in adipose tissue.

• 2.

  Insulin enhances entry of amino acids into muscles and cells – promotes protein synthesis in muscle, lipogenesis, hepatic and muscle glycogenesis.

• 3.

  Insulin also promotes peripheral utilization of glucose and K ⁺ uptake into the cells.

Actions of insulin. ⊕, stimulation; ⊖, inhibition.

Mechanism of action of insulin

Insulin binds to specific receptors (tyrosine kinase receptor) present on the cell membrane. The receptor consists of two α and two β subunits ( Fig. 9.23 ). The α subunits are entirely extracellular, whereas the β subunits are transmembrane proteins with tyrosine kinase activity. Binding of insulin to the α subunit activates tyrosine kinase activity of the β subunits resulting in phosphorylation of tyrosine residues of the receptor. This results in a complex series of phosphorylation–dephosphorylation reactions, which promotes entry of glucose into the cell and mediates various actions of insulin.

Mechanism of action of insulin.

Insulin preparations

Conventional insulin preparations

• 1.

  Bovine (beef) insulin: It differs from human insulin by three amino acid residues and is antigenic to man.

• 2.

  Porcine (pig) insulin: It differs from human insulin by only one amino acid residue and is less immunogenic than bovine insulin.

These preparations are antigenic as they contain pancreatic proteins, proinsulin, etc. Hence, they are not used.

Monocomponent insulins

Monocomponent insulins are purified insulins. They are less antigenic than conventional preparations, cause less insulin resistance and lipodystrophy at injection site, e.g. monocomponent porcine regular insulin, monocomponent porcine isophane insulin, etc.

(Purified insulins: insulin preparations with <10 ppm proinsulin contamination)

Human insulins

They are produced by recombinant DNA technology using Escherichia coli or yeast. They have the same amino acid sequence as endogenous insulin. They are least immunogenic; insulin resistance and lipodystrophy at the site of injection are rare, e.g. human regular insulin and human NPH insulin. Purified human insulins are the commonly used insulin preparations.

Insulin analogues

They are produced by DNA recombinant technology. The amino acid sequence is slightly different from endogenous insulin. Though actions are similar, pharmacokinetic profile is altered. They are either fast and short acting or slow and long acting.

Insulin is the main drug for all patients with type 1 DM, and for patients with type 2 DM who are not controlled by diet and oral antidiabetic drugs. The main goal of insulin therapy is to maintain the fasting blood glucose concentration between 90 and 120 mg/dL and postprandial glucose level below 150 mg/dL.

• 1.

  Sulphonylureas

  • (a)

    First generation: Tolbutamide

  • (b)

    Second generation: Glyburide (glibenclamide), glipizide, gliclazide, glimepiride

• 2.

  Biguanide: Metformin

• 3.

  Meglitinide analogue: Repaglinide

• 4.

  D-phenylalanine derivative: Nateglinide

• 5.

  Thiazolidinediones: Pioglitazone

• 6.

  α-Glucosidase inhibitors: Acarbose, miglitol, voglibose

• 7.

  Dipeptidyl peptidase-4 (DPP-4) inhibitors: Sitagliptin, saxagliptin, alogliptin, linagliptin, vildagliptin, teneligliptin

• 8.

  SGLT-2 (sodium–glucose co-transporter-2) inhibitor: Dapagliflozin, canagliflozin